Pregnancy represents a unique situation where environmental exposure to drugs and chemicals can affect the fetus as well as the mother. Unfortunately, even for many commonly used drugs, only qualitative or semiquantitative data on drug transfer characteristics are available in man. Pharmacokinetic characterization of placental drug transfer in humans is usually based on single point data obtained from different subjects at different times. Meaningful analysis of such data is difficult and results cannot be definitive. The relative exposure to the fetus is a function of placental transfer in both directions, distribution of the drug in the mother and fetus, and maternal and fetal elimination kinetics. While no animal model will precisely mimic the human model, there is no alternative but to use an animal model if rigorous kinetic information is to be collected. The specific aims of this proposal are (1) to study the placental transfer and drug disposition of labetalol in the pregnant ewe and fetal lamb and (2) to examine the effects of labetalol on maternal and fetal cardiorespiratory function in chronically instrumented awake pregnant ewes. Chronic indwelling catheters will be implanted into the maternal and fetal inferior vena cava, aorta and urinary bladder of ten pregnant ewes. Labetalol will be infused at constant rates to the mother and fetus, and steady-state maternal and fetal concentrations of labetalol will be determined by HPLC. Maternal and fetal cardiorespiratory parameters (heart rate, mean arterial pressure, PO2, PCO2, and pH), as well as uterine blood flow, will be continuously monitored during drug infusion. The data from this project will directly provide preliminary observations on the disposition and pharmacokinetic characteristics of labetalol in the pregnant ewe and fetal lamb. The correlation of this information with cardiorespiratory effects in the fetus may allow prediction of potential adverse effects in man. In addition, the experience gained in establishing a viable animal model which can be used to systematically study the pharmacokinetic and physiologic factors which modulate drug concentrations in the fetus is a prerequisite to future proposals. The knowledge gained from using this model in future studies may serve as a basis for designing dosage regimens and testing new pharmacologic agents which will produce maximal therapeutic efficacy with minimal toxicity in the fetus.